Clinical Trials /

High Dose IL 2 and Entinostat in RCC

NCT03501381

Description:

This is a multicenter, randomized, open label study of high dose interleukin 2 vs high dose interleukin 2 plus entinostat in clear cell RCC patients who are candidate for high dose interleukin 2. Patients will be randomized to ARM 1 (high dose interleukin 2 plus entinostat) or ARM 2 (high dose interleukin 2). Subjects will receive 2 treatments of high dose interleukin 600,000 units/kg administered IV every 8 hrs on Days 1-5 and Days 15-19 (maximum 28 doses) +/- entinostat 5 mg orally given every 2 weeks starting on Day-14, continuously. Tumor response assessment will be performed between HD IL-2 courses.

Related Conditions:
  • Clear Cell Renal Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: High Dose IL 2 and Entinostat in RCC
  • Official Title: A Phase II Randomized, Open Label Study of High Dose Interleukin 2 vs High Dose Interleukin 2 Plus Entinostat in Advanced Renal Cell Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: HCRN GU17-289
  • NCT ID: NCT03501381

Conditions

  • Renal Cell Carcinoma

Interventions

DrugSynonymsArms
EntinostatHigh Dose Interleukin 2 plus Entinostat
Interleukin-2aldesleukinHigh Dose Interleukin 2

Purpose

This is a multicenter, randomized, open label study of high dose interleukin 2 vs high dose interleukin 2 plus entinostat in clear cell RCC patients who are candidate for high dose interleukin 2. Patients will be randomized to ARM 1 (high dose interleukin 2 plus entinostat) or ARM 2 (high dose interleukin 2). Subjects will receive 2 treatments of high dose interleukin 600,000 units/kg administered IV every 8 hrs on Days 1-5 and Days 15-19 (maximum 28 doses) +/- entinostat 5 mg orally given every 2 weeks starting on Day-14, continuously. Tumor response assessment will be performed between HD IL-2 courses.

Trial Arms

NameTypeDescriptionInterventions
High Dose Interleukin 2Active ComparatorHD IL-2 600,000 IU/kg Every 8 hours on Days 1-5 and Days 15-19
  • Interleukin-2
High Dose Interleukin 2 plus EntinostatExperimentalHD IL-2 600,000 IU/kg Every 8 hours on Days 1-5 and Days 15-19 plus Entinostat 5 mg orally every 2 weeks starting Day -14
  • Entinostat
  • Interleukin-2

Eligibility Criteria

        Inclusion Criteria:

          -  Age ≥ 18 years at the time of consent.

          -  ECOG Performance Status of 0 within 7 days prior to registration.

          -  Life expectancy of greater than 6 months.

          -  Patients must have pathological diagnosis of renal cell carcinoma that is metastatic
             or surgically unresectable. The histology must be clear cell carcinoma or predominant
             clear cell carcinoma.

          -  Patients must have measurable or evaluable disease by RECIST 1.1.

          -  Up to two prior therapies for RCC are allowed. One prior therapy must contain an
             immune checkpoint inhibitor.Prior palliative radiation to metastatic lesion(s) is
             permitted, provided there is at least one measurable and/or evaluable lesion(s) that
             has not been irradiated

          -  White blood cell (WBC) ≥ 3,000 K/mm3

          -  Absolute Neutrophil Count (ANC) ≥ 1,500/mm3

          -  Leukocytes ≥ 3,000/mm3

          -  Platelets ≥ 100,000/mm3

          -  Hemoglobin (Hgb) ≥ 12 g/dL

          -  Serum creatinine ≤ 1.5 x upper limit of normal (ULN)

          -  Calculated creatinine clearance ≥ 50 mL/min

          -  Corrected calcium ≤ 10 mg/dL

          -  Urine protein < 1 +; if ≥ 1+, a 24 hour urine protein should be obtained and be <
             1,000 mg

          -  Total Bilirubin ≤ 1.5 × upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) ≤ 2.5 × ULN

          -  Alanine aminotransferase (ALT) ≤ 2.5 × ULN

          -  Lactate Dehydrogenase Within Normal Limits

          -  International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial
             Thromboplastin Time (aPTT) ≤ 1.5 × ULN

          -  Females of childbearing potential must have a negative serum pregnancy test during
             screening and within 3 days prior to receiving first dose of study medication. NOTE:
             Females are considered of child bearing potential unless they are surgically sterile
             (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy)
             or they are naturally postmenopausal for at least 12 consecutive months.

          -  Females of childbearing potential and males must be willing to abstain from
             heterosexual activity or to use 2 forms of effective methods of contraception from the
             time of informed consent until 90days after treatment discontinuation. The two
             contraception methods can be comprised of two barrier methods, or a barrier method
             plus a hormonal method.

          -  Pulmonary: FEV1 > 2.0 liters or > 75% of predicted for height and age

          -  Cardiac: No evidence of congestive heart failure, symptoms of coronary artery disease,
             myocardial infarction less than 6 months prior to entry, serious cardiac arrhythmias,
             or unstable angina. NOTE: Patients who are over 40 or have had previous myocardial
             infarction greater than 6 months prior to entry will be required to have a negative or
             low probability cardiac stress test for cardiac ischemia.

          -  CNS: No history of cerebrovascular accident, transient ischemic attacks, central
             nervous system or brain metastases. NOTE: Patients with CNS metastases should have a
             head CT/MRI within 21 days prior to treatment initiation. Any imaging abnormality
             indicative of CNS metastases will exclude the patient from the study. Patients with
             previously excised/gamma knifed solitary or oligometastases and no evidence of
             recurrent disease for 6 months are eligible.

        Exclusion Criteria:

          -  Concurrent use of valproic acid use is not allowed.

          -  Receiving medications that can effect clotting ability: warfarin, aspirin (once-daily
             aspirin use- maximum dose 325 mg/day is permitted), nonsteroidal anti-inflammatory
             drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole or
             clopidogrel, or similar agents.

          -  Patients may not be receiving other investigational agents.

          -  Active infection requiring systemic therapy

          -  Pregnant or breastfeeding

          -  Any prior history of other cancer within the prior 5 years with the exception of
             adequately treated basal cell carcinoma, cervical intraepithelial neoplasia
             [CIN]/cervical carcinoma in situ, melanoma in situ or ductal carcinoma in situ [DCIS],
             localized Gleason 6 prostate cancer, papillary thyroid cancer or other non-melanoma
             skin cancers.

          -  Any medical condition that would preclude adequate evaluation of the safety and
             toxicity of the study combination.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure (New York Association Class II, III,
             or IV), angina pectoris requiring nitrate therapy, recent myocardial infarction (< the
             last 6 months), cardiac arrhythmia, history of CVA within 6 months, hypertension
             (defined as blood pressure of >160 mmHg systolic and/or >90 mmHg diastolic on
             medication), QTc interval > 470 msec, history of peripheral vascular disease,
             uncontrolled diabetes mellitus, or psychiatric illness/social situations that would
             limit compliance with study

          -  HIV-positive patients receiving combination antiretroviral therapy are are eligible if
             their HIV is well-controlled (undetectable VL and CD4 count >350) and they are on
             anti-retrovirals unlikely to interact with entinostat.

          -  Known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C
             (e.g., hepatitis C virus ribonucleic acid [qualitative]). Patients with past hepatitis
             B virus (HBV) infection or resolved HBV infection (defined as the presence of
             hepatitis B core antibody [HBc Ab] and absence of HBsAg) are eligible. NOTE: HBV DNA
             test must be performed prior to study treatment. Patients positive for hepatitis C
             virus (HCV) antibody are eligible only if polymerase chain reaction is negative for
             HCV RNA.

          -  Serious or non-healing wound, ulcer or bone fracture.

          -  Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             prior to Day 1 therapy.

          -  Anticipation of need for major surgical procedures during the course of the study.

          -  Left ventricular ejection function < 45%.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free Survival (PFS)
Time Frame:24 months
Safety Issue:
Description:Compare PFS between arms. PFS is defined as the time from date of randomization until the criteria for disease progression is met as defined by RECIST 1.1 or death as a result of any cause.

Secondary Outcome Measures

Measure:Objective Response Rate
Time Frame:24 months
Safety Issue:
Description:Estimate and compare the objective response rate in patients receiving high dose interleukin 2 or high dose interleukin 2 plus entinostat. ORR will include confirmed complete response (CR) + confirmed partial response (PR) and will be determined as per RECIST 1.1.
Measure:Assess Adverse Events
Time Frame:24 months
Safety Issue:
Description:Assess the safety and tolerability of high dose interleukin 2 plus entinostat using CTCAE v4
Measure:Duration of response
Time Frame:24 months
Safety Issue:
Description:Assess duration of response in patients receiving high dose interleukin 2 or high dose interleukin 2 plus entinostat. Duration of overall response—the period measured from the time that measurement criteria are met for complete or partial response (whichever status is recorded first) until the date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since treatment started).
Measure:Overall Survival
Time Frame:24 Months
Safety Issue:
Description:Assess overall survival in patients receiving high dose interleukin 2 or high dose interleukin 2 plus entinostat. Overall survival is defined by the date of randomization to date of death from any cause.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Roberto Pili

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